EP1803440B1 - Pharmaceutical formulation comprising microcapsules of statins suspended in alkyl esters of polyunsaturated fatty asids (pufa) - Google Patents

Pharmaceutical formulation comprising microcapsules of statins suspended in alkyl esters of polyunsaturated fatty asids (pufa) Download PDF

Info

Publication number
EP1803440B1
EP1803440B1 EP05802903A EP05802903A EP1803440B1 EP 1803440 B1 EP1803440 B1 EP 1803440B1 EP 05802903 A EP05802903 A EP 05802903A EP 05802903 A EP05802903 A EP 05802903A EP 1803440 B1 EP1803440 B1 EP 1803440B1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical formulation
formulation according
microcapsules
previous
pufa
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Not-in-force
Application number
EP05802903A
Other languages
German (de)
French (fr)
Other versions
EP1803440A1 (en
Inventor
Paolo Carminati
Antonio Parente
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
GP Pharm SA
Defiante Farmaceutica SA
Original Assignee
GP Pharm SA
Defiante Farmaceutica SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by GP Pharm SA, Defiante Farmaceutica SA filed Critical GP Pharm SA
Priority to PL05802903T priority Critical patent/PL1803440T3/en
Priority to SI200531074T priority patent/SI1803440T1/en
Publication of EP1803440A1 publication Critical patent/EP1803440A1/en
Application granted granted Critical
Publication of EP1803440B1 publication Critical patent/EP1803440B1/en
Priority to CY20101100790T priority patent/CY1110751T1/en
Not-in-force legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5052—Proteins, e.g. albumin
    • A61K9/5057—Gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention describes a new pharmaceutical composition for the administration of statins and the process of preparing them.
  • statins in the primary and secondary prevention of cardiovascular diseases have been demonstrated in a number of clinical studies. Recent evidence suggests that the clinical benefit obtained with therapy with statins could be related to a reduction of systemic inflammatory markers ( Ridker P.M., et al.; N. Engl, J. Med. 344:1959-65, 2001 ) more than to the reduction of cholesterol level. Even though it has not been possible to prove that there is a direct relation of the anti-inflammatory mechanism of statins in the reduction of cardiovascular events, recent studies have shown that the treatment with statins improves plaque stability and reduces the arterial inflammatory reaction in patients subjected to endarterectomy ( Crisby M., et. al.; Circulation 103:926-33, 2001 ).
  • therapy with statins in experimental models determines the reduction of expressors of the inflammatory lesion, such as for example of the macrophage infiltration content ( Van der Wal A.C., et a).; Circulation 89:36-44, 1994 ), of the release of VCAM-1, of interleukin-1 ⁇ and of tissue factor in the arteriosclerotic lesion ( Sukhova GK, et al.; Arterioscler Thromb Vaso Biol 22:1452-8, 2002 ).
  • Omega-3 type polyunsaturated fatty acids have demonstrated a beneficial effect in the prevention of cardiovascular events ( Bucher HC, et al.; Am. J. Med. 2002; 112:298-304 ), possibly by means of an antiinflammatory, antithrombotic and antiarrhythmic mechanism ( Sethi S, et al.; Blood 2002:100:-1340-6 ; Billman GE, et al.; Circulation 1999: 99:2452-7 ).
  • statins such as for example:
  • a new formulation consisting of a microcapsule suspension of statins in alkyl esters of PUFA in which the statins are isolated from contact with the alkyl ester of PUFA by means of a polymeric membrane that can be easily disintegrated in the gastrointestinal medium.
  • This coating provides stabilization of the statin, eliminating the occurrence of degradation products of the statin during the processes of preparing the microcapsule suspension and of incorporating the mentioned microcapsule suspension of statins in alkyl esters of PUFA in final system of administering the product (soft gelatin capsules, hard gelatin capsules, tablets, granules, etc.), even though these processes are carried out at a temperature exceeding 40°C.
  • statins A new preparation for statins has been developed which surprisingly allows avoiding the problems of degradation that statins have when they are formulated in the presence of oils with a high content of alkyl esters of PUFA.
  • the present invention relates to a pharmaceutical formulation characterized in that it is made up of a suspension comprising an oil exceeding 60% in alkyl esters of polyunsaturated fatty acid (PUFA) and microcapsules comprising at least one polymer and a statin.
  • PUFA polyunsaturated fatty acid
  • Said alkyl esters of polyunsaturated fatty acid preferably belong to the Omega3 series, they are more preferably selected from the group consisting of the eicosapentaenoic acid, docosahexaenoic acid or mixtures thereof.
  • the alkyl ester of PUFA is selected from the group consisting of ethyl, methyl, propyl, butyl esters, or mixtures thereof.
  • statins selected from the group consisting of simvastatin, lovastatin, fluvastatin, atorvastatin, cerivastatin, pravastatin, rosuvastatin or mixtures thereof.
  • the polymer coating the microcapsules of statins is preferably selected from the group consisting of polyesters, polyacrylates, polycyanoacrylates, polysaccharides, polyethylene glycol, or mixtures thereof. More preferably, the polymer coating the microcapsules of statins is selected from the group consisting of gelatin, carboxymethylcellulose, alginates, carrageenans, pectins, ethyl cellulose hydroxypropyl methylcellulose, cellulose acetophthalate, hydroxypropyl methylcellulose phthalate, methylacrylic acid copolymers (Eudragit® L and S), dimethylaminoethylmethacrylate copolymers (Eudragit® E), the trimethylammoniumethylmethacrylate copolymers (Eudragit® RL and RS), polymers and copolymers of lactic and glycolic acids or mixtures thereof.
  • a pharmaceutical formulation according to the present invention comprises an antioxidant, preferably vitamin E acetate.
  • the pharmaceutical formulation comprises carnitine.
  • the microcapsules represent between 1% and 60% of the total weight of the pharmaceutical formulation according to the present invention, and the amount of statin incorporated in said microcapsules is comprised between 1% and 80% by weight, preferably between 1 and 40% by weight in relation to the total weight of the microcapsules.
  • the polymer comprises a plasticizer additive, preferably those plasticizers selected from the group consisting of triethyl citrate, butyl phthalate or mixtures thereof.
  • plasticizer additives preferably those plasticizers selected from the group consisting of triethyl citrate, butyl phthalate or mixtures thereof.
  • Other technical additives of the polymer can optionally be incorporated which improve or facilitate the encapsulation process, such as, for example, fluidizing agents, preferably talc.
  • the ratio between eicosapentaenoic acid and docosahexaenoic acid is preferably comprised between 0.5 and 2.
  • the microcapsule suspension is encapsulated by soft gelatin capsules for oral administration.
  • Said soft gelatin capsules preferably have an enteric coating.
  • microcapsules can be carried out following any of the methods described in the literature. By way of description and without being limited thereto, the different processes of obtaining microcapsules could be grouped into the following categories:
  • Example no. 1 Preparation of microcapsules of simvastatin with gelatin and carboxymethyl cellulose by means of complex coacervation processes.
  • Solution A A 1% solution of gelatin in water is prepared and the pH is adjusted so that it is equal to or greater than 7.
  • Solution B Another 1% solution of sodium carboxymethyl cellulose in water is prepared and the pH is adjusted so that it is equal to or greater than 7.
  • the resulting suspension is dried by means of spray drying, obtaining a microcapsules powder containing 37% of simvastatin.
  • This microcapsule powder is directly dispersed in oil containing 88% ethyl ester of PUFA with an eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA) ratio of 1.2.
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • Example no. 2 Preparation of microcapsules of simvastatin with gelatin by means of simple coacervation processes.
  • a 1 % solution of gelatin in water is prepared.
  • simvastatin 100 mL of this solution are taken and 1 g of powder simvastatin is dispersed therein. Once all the simvastatin has been dispersed 30 mL of a saturated solution of sodium sulfate in water are added. It is maintained under stirring for 1 hour and 0.5 mL of a 50% solution of glutaraldehyde in water are added.
  • the formed microcapsules are collected by filtration, washed with water and dried in a vacuum oven.
  • the simvastatin content of these microcapsules is 45%.
  • microcapsule powder is dispersed directly in oil containing 70% of methyl ester of PUFA with an EPA/DHA ratio of 0.8.
  • Example no. 3 Preparation of microcapsules of lovastatin with polyethylene glycol.
  • a 10% solution of polyethylene glycol in water with molecular weight 35000 (PEG-35000) is prepared.
  • the solution is dried by means of spray drying.
  • the obtained microcapsule powder has a 40% lovastatin concentration and is dispersed directly in oil containing 85% of ethyl ester of PUFA with an EPA/DHA ratio of 1.
  • Example no. 4 Preparation of microcapsules of simvastatin with cellulose acetophthalate.
  • a 2% solution of sodium acetophthalate in water is prepared. 5 g of simvastatin powder are suspended in 100 mL of this solution. The resulting suspension is dried by means of spray drying.
  • microcapsule powder is dispersed directly in oil containing 85% of ethyl ester of PUFA with an EPA/DHA ratio of 0.5.
  • Example no. 5 Preparation of microcapsules of simvastatin with poly(lactic-glycolic acid) (PLGA) copolymer and vitamin E. Simple emulsion method (oil in water)
  • Solution A A 10% solution of PLGA in dichloromethane (DCM) with intrinsic viscosity (I.V.) of 0.17 and lactic/glycolic ratio of 1/1 is prepared.
  • Solution B 5 g of simvastatin and 1 g of vitamin E acetate are dissolved in 100 mL of solution A.
  • Solution C A 1 % solution of polyvinyl alcohol (PVA) in water is prepared.
  • the resulting powder is dispersed directly in oil containing 85% of ethyl ester of PUFA with an EPA/DHA ratio of 1.5.
  • Example no. 6 Preparation of microcapsules of simvastatin with carnitine and polyethylene glycol
  • a 10% solution of polyethylene glycol in water with molecular weight 35000 (PEG-35000) is prepared.
  • microcapsule powder is dispersed directly in oil containing 85% of ethyl ester of PUFA with an EPA/DHA ratio of 1.
  • Example no. 7 Preparation of microcapsules of simvastatin with carnitine, vitamin E and PLGA, triple emulsion method (water in oil and in water.)
  • Solution A A 10% solution of carnitine in water is prepared.
  • Solution B A 10% solution of PLGA in dichloromethane (DCM) with intrinsic viscosity (I.V.) of 0.17 and lactic/glycolic ratio 1/1 is prepared.
  • DCM dichloromethane
  • I.V. intrinsic viscosity
  • Solution C 10 g of simvastatin and 1 g of vitamin E acetate are dissolved in 100 mL of solution B.
  • a microcapsule powder is obtained which is washed with abundant water to eliminate the excess PVA and is dried under reduced pressure in a vacuum oven.
  • the resulting microcapsule powder has a simvastatin concentration of 25% and is dispersed directly in oil containing 85% of ethyl ester of PUFA with an EPA/DHA ratio of 1.2.
  • Example no. 8 Preparation of microcapsules of simvastatin and a methacrylic acid copolymer
  • simvastatin 10 g are suspended in 100 mL of a suspension of Eudragit FS 30D ® (30% suspension in water of copolymers of methacrylic acid, methyl methacrylic acid and methyl acrylate) until obtaining a fine suspension.
  • Triethyl citrate plasticizer of the polymer is added to this suspension up to a concentration of 5%.
  • the resulting suspension is dried by means of spray drying.
  • microcapsule powder is dispersed directly in oil containing 85% of ethyl ester of PUFA with an EPA/DHA ratio of 1.2.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Dispersion Chemistry (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a pharmaceutical composition comprising a suspension consisting of an oil with a high concentration of alkyl esters of polyunsaturated fatty acids (PUFA) and to microcapsules comprising at least one polymer and a statin.

Description

    State of the Art
  • The present invention describes a new pharmaceutical composition for the administration of statins and the process of preparing them.
  • The efficacy of the statins in the primary and secondary prevention of cardiovascular diseases has been demonstrated in a number of clinical studies. Recent evidence suggests that the clinical benefit obtained with therapy with statins could be related to a reduction of systemic inflammatory markers (Ridker P.M., et al.; N. Engl, J. Med. 344:1959-65, 2001) more than to the reduction of cholesterol level. Even though it has not been possible to prove that there is a direct relation of the anti-inflammatory mechanism of statins in the reduction of cardiovascular events, recent studies have shown that the treatment with statins improves plaque stability and reduces the arterial inflammatory reaction in patients subjected to endarterectomy (Crisby M., et. al.; Circulation 103:926-33, 2001). In addition, therapy with statins in experimental models determines the reduction of expressors of the inflammatory lesion, such as for example of the macrophage infiltration content (Van der Wal A.C., et a).; Circulation 89:36-44, 1994), of the release of VCAM-1, of interleukin-1β and of tissue factor in the arteriosclerotic lesion (Sukhova GK, et al.; Arterioscler Thromb Vaso Biol 22:1452-8, 2002).
  • Omega-3 type polyunsaturated fatty acids (Ω-3 PUFA) have demonstrated a beneficial effect in the prevention of cardiovascular events (Bucher HC, et al.; Am. J. Med. 2002; 112:298-304), possibly by means of an antiinflammatory, antithrombotic and antiarrhythmic mechanism (Sethi S, et al.; Blood 2002:100:-1340-6; Billman GE, et al.; Circulation 1999: 99:2452-7).
  • It is also disclosed in the state of the art (Salvi A., et al.; Curr. Ther. Res. 53(6): 717-21) a combination therapy of simvastatin with fish oil, where both drugs are administered in two separated oral capsules. There is no indication in this document about a common capsule for both drugs together.
  • Different patents have been published which describe pharmaceutical formulations of statins, such as for example:
    • US 5,180,589 or US 5,356,896 which describe pharmaceutical composition forms for the stabilization of statins at low pH.
    • US 6,235,311 describes a pharmaceutical composition combining a statin and aspirin.
    • US 5,225,202 describes a pharmaceutical composition of statins in the form of pellets with an enteric coating so as to protect the product at low pH.
    • WO00/76482 , WO00/57918 and WO00/57859 describe pharmaceutical compositions formed by lipid regulating agents in oils or in surfactants.
    • WO02/100394 and WO03/103640 describe pharmaceutical compositions formed by pure statin nanoparticles without any protective coating dispersed in pharmaceutically acceptable oils, however this type of formulations have stability problems for statins if the temperature of preparing the system exceeds 40°C, as is the case for most oral preparations. Particularly in WO03/103640 , the pharmaceutically acceptable oil can be a fish oil. However, the stability problems of the pharmaceutical composition disclosed in WO02/100394 are not mentioned, neither solved, in WO03/10364 .
    Summary of the Invention
  • As a result of the research carried out by the inventors, a new formulation has been developed consisting of a microcapsule suspension of statins in alkyl esters of PUFA in which the statins are isolated from contact with the alkyl ester of PUFA by means of a polymeric membrane that can be easily disintegrated in the gastrointestinal medium.
  • This coating provides stabilization of the statin, eliminating the occurrence of degradation products of the statin during the processes of preparing the microcapsule suspension and of incorporating the mentioned microcapsule suspension of statins in alkyl esters of PUFA in final system of administering the product (soft gelatin capsules, hard gelatin capsules, tablets, granules, etc.), even though these processes are carried out at a temperature exceeding 40°C.
    • Detailed Description of the Invention
  • A new preparation for statins has been developed which surprisingly allows avoiding the problems of degradation that statins have when they are formulated in the presence of oils with a high content of alkyl esters of PUFA.
  • Therefore, according to a first essential aspect, the present invention relates to a pharmaceutical formulation characterized in that it is made up of a suspension comprising an oil exceeding 60% in alkyl esters of polyunsaturated fatty acid (PUFA) and microcapsules comprising at least one polymer and a statin.
  • Said alkyl esters of polyunsaturated fatty acid (PUFA) preferably belong to the Omega3 series, they are more preferably selected from the group consisting of the eicosapentaenoic acid, docosahexaenoic acid or mixtures thereof.
  • According to a preferred embodiment according to the present invention, the alkyl ester of PUFA is selected from the group consisting of ethyl, methyl, propyl, butyl esters, or mixtures thereof.
  • Preferably, the statins selected from the group consisting of simvastatin, lovastatin, fluvastatin, atorvastatin, cerivastatin, pravastatin, rosuvastatin or mixtures thereof.
  • The polymer coating the microcapsules of statins is preferably selected from the group consisting of polyesters, polyacrylates, polycyanoacrylates, polysaccharides, polyethylene glycol, or mixtures thereof. More preferably, the polymer coating the microcapsules of statins is selected from the group consisting of gelatin, carboxymethylcellulose, alginates, carrageenans, pectins, ethyl cellulose hydroxypropyl methylcellulose, cellulose acetophthalate, hydroxypropyl methylcellulose phthalate, methylacrylic acid copolymers (Eudragit® L and S), dimethylaminoethylmethacrylate copolymers (Eudragit® E), the trimethylammoniumethylmethacrylate copolymers (Eudragit® RL and RS), polymers and copolymers of lactic and glycolic acids or mixtures thereof.
  • Optionally, a pharmaceutical formulation according to the present invention comprises an antioxidant, preferably vitamin E acetate. According to a preferred embodiment according to the present invention, the pharmaceutical formulation comprises carnitine.
  • Preferably, the microcapsules represent between 1% and 60% of the total weight of the pharmaceutical formulation according to the present invention, and the amount of statin incorporated in said microcapsules is comprised between 1% and 80% by weight, preferably between 1 and 40% by weight in relation to the total weight of the microcapsules.
  • According to a preferred embodiment according to the present invention, the polymer comprises a plasticizer additive, preferably those plasticizers selected from the group consisting of triethyl citrate, butyl phthalate or mixtures thereof. Other technical additives of the polymer can optionally be incorporated which improve or facilitate the encapsulation process, such as, for example, fluidizing agents, preferably talc.
  • The ratio between eicosapentaenoic acid and docosahexaenoic acid is preferably comprised between 0.5 and 2.
  • According to a preferred embodiment of the present invention, the microcapsule suspension is encapsulated by soft gelatin capsules for oral administration. Said soft gelatin capsules preferably have an enteric coating.
  • The preparation of the microcapsules can be carried out following any of the methods described in the literature. By way of description and without being limited thereto, the different processes of obtaining microcapsules could be grouped into the following categories:
    1. A) Simple coacervation methods:
      • A solution of the polymer together with the possible additives of the polymer in a suitable solvent is prepared. The drug to be encapsulated is suspended in said solution of the polymer and a non-solvent of the polymer is added so as to force the deposit of the polymer on the drug crystals. Examples of these processes can be found in patent documents such as ES 2009346 , EP 0 052 510 , or EP 0 346 879 .
    2. B) Complex coacervation method
      This method is based on the interaction between two colloids having opposite electric charges so as to generate an insoluble complex that is deposited on the particles of the drug to be encapsulated, forming a membrane that will isolate the drug. Examples of these processes can be found in patent documents such as GB 1393805 .
    3. C) Double emulsion methods:
      • The drug to be encapsulated is dissolved in water or in a solution of some other coadyuvant and is emulsified in a solution of the polymer and additives in a suitable solvent, such as for example dichloromethane. The resulting emulsion is in turn emulsified in water or in an aqueous solution of an emulsifying agent, such as polyvinyl alcohol. Once this second emulsion is carried out the solvent in which the polymer and the plasticizer were dissolved in is eliminated by means of evaporation or extraction. The resulting microcapsules are obtained directly by filtration or evaporation. Examples of these processes can also be found in patent documents such as US 4,652,441 .
    4. D) Simple emulsion methods:
      • The drug to be encapsulated, the polymer and the additives are dissolved together in a suitable solvent. This solution is emulsified in water or in an emulsifier solution, such as polyvinyl alcohol, and the organic solvent is eliminated by evaporation or by extraction. The resulting microcapsules are recovered by filtration or drying. Examples of these processes can also be found in patent documents such as US 5,445,832
    5. E) Solvent evaporation methods:
      • The drug to be encapsulated, the polymer and additives are dissolved together in a suitable solvent. This solution is evaporated and the resulting residue is micronized to the suitable size. Examples of this process can also be found in patent documents such as GB 2,209,937 .
    EXAMPLES: Example no. 1: Preparation of microcapsules of simvastatin with gelatin and carboxymethyl cellulose by means of complex coacervation processes.
  • Solution A: A 1% solution of gelatin in water is prepared and the pH is adjusted so that it is equal to or greater than 7.
  • Solution B: Another 1% solution of sodium carboxymethyl cellulose in water is prepared and the pH is adjusted so that it is equal to or greater than 7.
  • 100 mL of solution A and 100 mL of solution B are mixed and heated to 40°C. 1.2 g of powder simvastatin are dispersed in the mixture. When all the powder is dispersed and no lumps are observed, the pH is adjusted to 4.0 by means of adding acetic acid. It is maintained under stirring for 1 hour at 40°C and then the solution is cooled to 10°C, this temperature being maintained for another hour. 1 mL of a 50% solution of glutaraldehyde in water is added.
  • The resulting suspension is dried by means of spray drying, obtaining a microcapsules powder containing 37% of simvastatin.
  • This microcapsule powder is directly dispersed in oil containing 88% ethyl ester of PUFA with an eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA) ratio of 1.2.
    • Example no. 2: Preparation of microcapsules of simvastatin with gelatin by means of simple coacervation processes.
  • A 1 % solution of gelatin in water is prepared.
  • 100 mL of this solution are taken and 1 g of powder simvastatin is dispersed therein. Once all the simvastatin has been dispersed 30 mL of a saturated solution of sodium sulfate in water are added. It is maintained under stirring for 1 hour and 0.5 mL of a 50% solution of glutaraldehyde in water are added.
  • The formed microcapsules are collected by filtration, washed with water and dried in a vacuum oven. The simvastatin content of these microcapsules is 45%.
  • The resulting microcapsule powder is dispersed directly in oil containing 70% of methyl ester of PUFA with an EPA/DHA ratio of 0.8.
    • Example no. 3: Preparation of microcapsules of lovastatin with polyethylene glycol.
  • A 10% solution of polyethylene glycol in water with molecular weight 35000 (PEG-35000) is prepared.
  • 6 g of lovastatin are dispersed in this solution by means of intense stirring.
  • When a fine dispersion without lumps has been obtained, the solution is dried by means of spray drying.
  • The obtained microcapsule powder has a 40% lovastatin concentration and is dispersed directly in oil containing 85% of ethyl ester of PUFA with an EPA/DHA ratio of 1.
    • Example no. 4: Preparation of microcapsules of simvastatin with cellulose acetophthalate.
  • A 2% solution of sodium acetophthalate in water is prepared. 5 g of simvastatin powder are suspended in 100 mL of this solution. The resulting suspension is dried by means of spray drying.
  • The obtained microcapsule powder is dispersed directly in oil containing 85% of ethyl ester of PUFA with an EPA/DHA ratio of 0.5.
    • Example no. 5: Preparation of microcapsules of simvastatin with poly(lactic-glycolic acid) (PLGA) copolymer and vitamin E. Simple emulsion method (oil in water)
  • Solution A: A 10% solution of PLGA in dichloromethane (DCM) with intrinsic viscosity (I.V.) of 0.17 and lactic/glycolic ratio of 1/1 is prepared.
  • Solution B: 5 g of simvastatin and 1 g of vitamin E acetate are dissolved in 100 mL of solution A.
  • Solution C: A 1 % solution of polyvinyl alcohol (PVA) in water is prepared.
  • 100 mL of solution B are added slowly and under intense stirring to 1000 mL of solution C until obtaining a milky emulsion.
  • While stirring is maintained, a nitrogen current is passed through the previous emulsion for two hours to eliminate most of the DCM.
  • Then the resulting suspension is frozen and lyophilized. A powder is obtained which is washed with abundant water to eliminate the excess PVA and is dried under reduced pressure.
  • The resulting powder is dispersed directly in oil containing 85% of ethyl ester of PUFA with an EPA/DHA ratio of 1.5.
    • Example no. 6: Preparation of microcapsules of simvastatin with carnitine and polyethylene glycol
  • A 10% solution of polyethylene glycol in water with molecular weight 35000 (PEG-35000) is prepared.
  • 5 g of simvastatin and 1 g of carnitine are dispersed in this solution by means of intense stirring. When a fine dispersion without lumps has been obtained the solution is dried by means of spray drying.
  • The obtained microcapsule powder is dispersed directly in oil containing 85% of ethyl ester of PUFA with an EPA/DHA ratio of 1.
    • Example no. 7: Preparation of microcapsules of simvastatin with carnitine, vitamin E and PLGA, triple emulsion method (water in oil and in water.)
  • Solution A: A 10% solution of carnitine in water is prepared.
  • Solution B: A 10% solution of PLGA in dichloromethane (DCM) with intrinsic viscosity (I.V.) of 0.17 and lactic/glycolic ratio 1/1 is prepared.
  • Solution C. 10 g of simvastatin and 1 g of vitamin E acetate are dissolved in 100 mL of solution B.
  • 20 mL of solution A are emulsified in solution C by means of intense stirring with an Ultra Turrax homogenizer. The resulting emulsion is in turn emulsified in 1000 mL of a 1 % solution of PVA in water.
  • While stirring is maintained, a nitrogen current is passed through the previous emulsion for two hours to eliminate most of the DCM.
  • Then the resulting suspension is frozen and lyophilized. A microcapsule powder is obtained which is washed with abundant water to eliminate the excess PVA and is dried under reduced pressure in a vacuum oven.
  • The resulting microcapsule powder has a simvastatin concentration of 25% and is dispersed directly in oil containing 85% of ethyl ester of PUFA with an EPA/DHA ratio of 1.2.
    • Example no. 8: Preparation of microcapsules of simvastatin and a methacrylic acid copolymer
  • 10 g of simvastatin are suspended in 100 mL of a suspension of Eudragit FS 30D® (30% suspension in water of copolymers of methacrylic acid, methyl methacrylic acid and methyl acrylate) until obtaining a fine suspension. Triethyl citrate (plasticizer of the polymer) is added to this suspension up to a concentration of 5%.
  • The resulting suspension is dried by means of spray drying.
  • The resulting microcapsule powder is dispersed directly in oil containing 85% of ethyl ester of PUFA with an EPA/DHA ratio of 1.2.

Claims (18)

  1. A pharmaceutical formulation characterized in that it is made up of a suspension comprising an oil, exceeding 60% in alkyl esters of polyunsaturated fatty acid (PUFA) and microcapsules comprising at least one polymer and a statin, said statin being isolated from the contact with said alkyl esters of PUFA by a polymeric membrane that can be easily disintegrated in the gastrointestinal medium.
  2. A pharmaceutical formulation according to claim 1, characterized in that the PUFA belongs to the Omega3 series.
  3. A pharmaceutical formulation according to any of the previous claims,
    characterized in that the PUFA is selected from the group consisting of eicosapentaenoic acid, the docosahexaenoic acid or mixtures thereof.
  4. A pharmaceutical formulation according to any of the previous claims,
    characterized in that the alkyl ester of PUFA is selected from the group consisting of ethyl, methyl, propyl, butyl esters or mixtures thereof.
  5. A pharmaceutical formulation according to any of the previous claims,
    characterized in that the statins are selected from the group consisting of simvastatin, lovastatin, fluvastatin, atorvastatin, cerivastatin, pravastatin, rosuvastatin or mixtures thereof.
  6. A pharmaceutical formulation according to any of the previous claims,
    characterized in that the polymer coating the microcapsules of statins is selected from the group consisting of polyesters, polyacrylates, polycyanoacrylates, polysaccharides, polyethylene glycol, or mixtures thereof.
  7. A pharmaceutical formulation according to any of the previous claims,
    characterized in that the polymer coating the microcapsules of statins is selected from the group consisting of gelatin, carboxymethylcellulose, alginates, carrageenans, pectins, ethyl cellulose, hydroxypropyl methylcellulose, cellulose acetophthalate, hydroxypropyl methylcellulose phthalate, methacrylic acid copolymers, dimethylaminoethylmethacrylate copolymers, trimethylammoniumethylmethacrylate copolymers, lactic and glycolic acid polymers and copolymers or mixtures thereof.
  8. A pharmaceutical formulation according to any of the previous claims,
    characterized in that it further comprises an antioxidant
  9. A pharmaceutical formulation according to claim 8, characterized in that said antioxidant is vitamin E acetate.
  10. A pharmaceutical formulation according to any of the previous claims,
    characterized in that it further comprises carnitine.
  11. A pharmaceutical formulation according to any of the previous claims,
    characterized in that the microcapsules represent between 1% and 60% of the total weight of the formulation.
  12. A pharmaceutical formulation according to any of the previous claims,
    characterized in that the amount of statin incorporated in the microcapsules is comprised between 1% and 80% by weight in relation to the total weight of the microcapsules.
  13. A pharmaceutical formulation according to claim 12, characterized in that said amount of statin incorporated in the microcapsules is comprised between 1 and 40% by weight in relation to the total weight of the microcapsules.
  14. A pharmaceutical formulation according to any of the previous claims
    characterized in that it further comprises a plasticizer additive of the polymer
  15. A pharmaceutical formulation according to claim 14, characterized in that said plasticizer additive is selected from the group consisting on triethyl citrate, butyl phthalate and mixtures thereof.
  16. A pharmaceutical formulation according to any of claims 3-15,
    characterized in that the ratio between eicosapentaenoic acid and docosahexaenoic acid is comprised between 0.5 and 2.
  17. Any formulation of the previous claims, characterized in that the microcapsule suspension is encapsulated by soft gelatin capsules for oral administration.
  18. A formulation according to claim 17, characterized in that the soft gelatin capsules have an enteric coating.
EP05802903A 2004-10-19 2005-10-13 Pharmaceutical formulation comprising microcapsules of statins suspended in alkyl esters of polyunsaturated fatty asids (pufa) Not-in-force EP1803440B1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
PL05802903T PL1803440T3 (en) 2004-10-19 2005-10-13 Pharmaceutical formulation comprising microcapsules of statins suspended in alkyl esters of polyunsaturated fatty asids (pufa)
SI200531074T SI1803440T1 (en) 2004-10-19 2005-10-13 Pharmaceutical formulation comprising microcapsules of statins suspended in alkyl esters of polyunsaturated fatty asids (pufa)
CY20101100790T CY1110751T1 (en) 2004-10-19 2010-08-30 PHARMACEUTICAL FORM INCLUDING MICROCELLULARS FROM STATINES DISTRIBUTED IN ALUYLIC Fatty Acid (PUFA)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ES200402492A ES2255426B1 (en) 2004-10-19 2004-10-19 PHARMACEUTICAL FORMULATION THAT INCLUDES MICROCAPSULES OF STATINS SUSPENDED IN ESTER ALKYLS OF POLYINSATURATED FATTY ACIDS (PUFA).
PCT/ES2005/000542 WO2006045865A1 (en) 2004-10-19 2005-10-13 Pharmaceutical formulation comprising microcapusles of statins suspended in alkyl esters of polyunsaturated fatty acids (pufa)

Publications (2)

Publication Number Publication Date
EP1803440A1 EP1803440A1 (en) 2007-07-04
EP1803440B1 true EP1803440B1 (en) 2010-06-02

Family

ID=36227494

Family Applications (1)

Application Number Title Priority Date Filing Date
EP05802903A Not-in-force EP1803440B1 (en) 2004-10-19 2005-10-13 Pharmaceutical formulation comprising microcapsules of statins suspended in alkyl esters of polyunsaturated fatty asids (pufa)

Country Status (22)

Country Link
US (1) US20090196920A1 (en)
EP (1) EP1803440B1 (en)
JP (1) JP4976302B2 (en)
KR (1) KR101413339B1 (en)
CN (2) CN102727462A (en)
AT (1) ATE469641T1 (en)
AU (1) AU2005298587B2 (en)
BR (1) BRPI0516152A (en)
CA (1) CA2583756C (en)
CY (1) CY1110751T1 (en)
DE (1) DE602005021668D1 (en)
DK (1) DK1803440T3 (en)
EA (1) EA012371B1 (en)
ES (2) ES2255426B1 (en)
IL (1) IL182466A (en)
MX (1) MX2007004655A (en)
NZ (1) NZ554265A (en)
PL (1) PL1803440T3 (en)
PT (1) PT1803440E (en)
SI (1) SI1803440T1 (en)
WO (1) WO2006045865A1 (en)
ZA (1) ZA200703509B (en)

Families Citing this family (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BRPI0610344A2 (en) 2005-12-13 2016-11-29 Teva Pharma crystallized form of atorvastatin hemi-calcium, process for its preparation, derived pharmaceutical product and its medicinal use
US8784886B2 (en) 2006-03-09 2014-07-22 GlaxoSmithKline, LLC Coating capsules with active pharmaceutical ingredients
SI2018153T1 (en) * 2006-04-26 2012-08-31 Rosemont Pharmaceuticals Ltd Liquid oral compositions
EP2046305A2 (en) * 2006-06-26 2009-04-15 Valpharma S.A. Pharmaceutical composition for the oral administration of omega polyenoic fatty acids
EP2037894A2 (en) * 2006-07-06 2009-03-25 Teva Pharmaceutical Industries Ltd. Compositions with controlled pharmacokinetics
ITMI20072142A1 (en) 2007-11-08 2009-05-09 Yervant Zarmanian PHARMACEUTICAL COMPOSITIONS CONTAINING STATIN AND OMEGA-3 FATTY ACID DERIVATIVES
GB0724735D0 (en) 2007-12-19 2008-01-30 Psynova Neurotech Ltd Methods and biomarkers for diagnosing and monitoring psychotic disorders
KR20100111292A (en) * 2008-01-10 2010-10-14 다케다 야쿠힌 고교 가부시키가이샤 Capsule formulation
GB0818472D0 (en) * 2008-10-08 2008-11-12 Probio Nutraceuticals As Composition
GB0818473D0 (en) 2008-10-08 2008-11-12 Probio Nutraceuticals As Composition
ITFI20080243A1 (en) * 2008-12-15 2010-06-16 Valpharma Sa FORMULATIONS FOR ORAL ADMINISTRATION OF OMEGA POLIENOIC FATTY ACIDS IN COMBINATION WITH NATURAL OR SEMI-SYNTHETIC STATINES.
NZ720946A (en) 2009-04-29 2017-09-29 Amarin Pharmaceuticals Ie Ltd Pharmaceutical compositions comprising epa and a cardiovascular agent and methods of using the same
ES2364011B1 (en) * 2009-11-20 2013-01-24 Gp Pharm, S.A. CAPSULES OF PHARMACEUTICAL ACTIVE AND ESTERS OF POLYINSATURATED FATTY ACIDS FOR THE TREATMENT OF CARDIOVASCULAR DISEASES.
ES2363965B1 (en) * 2009-11-20 2013-01-24 Gp Pharm S.A. CAPSULES OF BETABLOCKING ACTIVE PRINCIPLES AND ESTERS OF POLYINSATURATED FATTY ACIDS.
ES2363964B1 (en) * 2009-11-20 2012-08-22 Gp Pharm, S.A. CAPSULES OF PHARMACEUTICAL ACTIVE PRINCIPLES AND ESTERS OF POLYINSATURATED FATTY ACIDS.
WO2011078712A1 (en) * 2009-12-23 2011-06-30 Dafiante Farmacêutica S.A. Combination composition useful for treating cardiovascular diseases
CA2706270C (en) * 2010-06-03 2020-01-07 Accucaps Industries Limited Pharmaceutical formulations of statins and omega-3 fatty acids for encapsulation
CA3065589C (en) * 2010-06-03 2022-04-26 Catalent Ontario Limited Multi phase soft gel capsules, apparatus and method thereof
CA2803558C (en) 2010-06-30 2018-05-29 Mochida Pharmaceutical Co., Ltd. .omega.3 fatty acid compound preparation
US9107983B2 (en) 2010-10-27 2015-08-18 Warsaw Orthopedic, Inc. Osteoconductive matrices comprising statins
US8877221B2 (en) 2010-10-27 2014-11-04 Warsaw Orthopedic, Inc. Osteoconductive matrices comprising calcium phosphate particles and statins and methods of using the same
AU2011336856A1 (en) 2010-11-29 2013-07-04 Amarin Pharmaceuticals Ireland Limited Low eructation composition and methods for treating and/or preventing cardiovascular disease in a subject with fish allergy/hypersensitivity
US11712429B2 (en) 2010-11-29 2023-08-01 Amarin Pharmaceuticals Ireland Limited Low eructation composition and methods for treating and/or preventing cardiovascular disease in a subject with fish allergy/hypersensitivity
KR101310710B1 (en) * 2011-03-23 2013-09-27 한미약품 주식회사 Oral complex composition comprising omega-3 fatty acid ester and hmg-coa reductase inhibitor
US9308190B2 (en) 2011-06-06 2016-04-12 Warsaw Orthopedic, Inc. Methods and compositions to enhance bone growth comprising a statin
KR101466617B1 (en) * 2011-11-17 2014-11-28 한미약품 주식회사 ORAL COMPLEX FORMULATION COMPRISING OMEGA-3 FATTY ACID AND HMG-CoA REDUCTASE INHIBITOR WITH IMPROVED STABILITY
EP2846779A4 (en) * 2012-05-07 2015-12-16 Omthera Pharmaceuticals Inc Compositions of statins and omega-3 fatty acids
BR112014029079B1 (en) 2012-05-22 2022-07-26 Kuhnil Pharm. Co., Ltd PHARMACEUTICAL COMPOSITION FOR ORAL ADMINISTRATION
CN102824636A (en) * 2012-08-15 2012-12-19 四川大学 Pharmaceutical composition containing statins and polyunsaturated fatty acid and application thereof
WO2014182003A1 (en) * 2013-05-06 2014-11-13 Hanmi Pharm. Co., Ltd. Composite formulation comprising a film coating layer containing rosuvastatin or a pharmaceutically acceptable salt thereof
KR102240429B1 (en) * 2013-05-06 2021-04-15 한미약품 주식회사 Composite formulation comprising a film coating layer containing rosuvastatin or a pharmaceutically acceptable salt thereof
WO2015185240A1 (en) 2014-06-04 2015-12-10 Sigma-Tau Industrire Farmaceutiche Riunite S.P.A. Compositions containing simvastatin in omega-3 polyunsaturated fatty acids
RU2614734C2 (en) * 2015-05-21 2017-03-28 Татьяна Алексеевна Денисюк Method of producing nanocapsules of rosuvastatin in carrageenan
KR101950907B1 (en) 2016-02-05 2019-02-21 한국유나이티드제약 주식회사 Oral preparation comprising liphophilic drug and a oilproof material coated solid formulation
WO2019143981A1 (en) * 2018-01-19 2019-07-25 Arizona Board Of Regents On Behalf Of The University Of Arizona Compositions and methods for delivering pharmaceutical agents
MA51766A (en) 2018-09-24 2020-12-16 Amarin Pharmaceuticals Ie Ltd METHODS OF REDUCING THE RISK OF CARDIOVASCULAR EVENTS IN A SUBJECT
WO2022129002A1 (en) * 2020-12-15 2022-06-23 Dsm Ip Assets B.V. Coarse dispersion comprising statin and vitamin e oil
KR20240012390A (en) 2021-04-21 2024-01-29 애머린 파마슈티칼스 아일랜드 리미티드 How to Reduce Your Risk of Heart Failure

Family Cites Families (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5312473B1 (en) 1971-05-24 1978-05-01
PH19942A (en) 1980-11-18 1986-08-14 Sintex Inc Microencapsulation of water soluble polypeptides
JPS60100516A (en) 1983-11-04 1985-06-04 Takeda Chem Ind Ltd Preparation of sustained release microcapsule
GB2209937B (en) 1987-09-21 1991-07-03 Depiopharm S A Water insoluble polypeptides
US5180589A (en) 1988-03-31 1993-01-19 E. R. Squibb & Sons, Inc. Pravastatin pharmaceuatical compositions having good stability
US5035896A (en) 1988-06-15 1991-07-30 Warner-Lambert Company Water insoluble drugs coated by coacervated fish gelatin
CH683149A5 (en) * 1991-07-22 1994-01-31 Debio Rech Pharma Sa Process for the preparation of microspheres of a biodegradable polymeric material.
US5225202A (en) * 1991-09-30 1993-07-06 E. R. Squibb & Sons, Inc. Enteric coated pharmaceutical compositions
HU9203780D0 (en) 1991-12-12 1993-03-29 Sandoz Ag Stabilized pharmaceutical products of hmg-coa reductase inhibitor and method for producing them
US5861399A (en) * 1996-07-17 1999-01-19 Heart Care Partners Methods and compositions for the rapid and enduring relief of inadequate myocardial function
US6235311B1 (en) * 1998-03-18 2001-05-22 Bristol-Myers Squibb Company Pharmaceutical composition containing a combination of a statin and aspirin and method
AU4021100A (en) 1999-03-31 2000-10-16 Abbott Laboratories Novel formulations comprising lipid-regulating agents
MXPA01009839A (en) 1999-03-31 2002-06-21 Abbott Lab Novel formulations comprising lipid-regulating agents.
US6372251B2 (en) 1999-06-11 2002-04-16 Abbott Laboratories Formulations comprising lipid-regulating agents
US7208180B2 (en) * 2000-05-08 2007-04-24 N.V. Nutricia Method and preparation for the preventing and/or treating vascular disorders and secondary disorders associated therewith
US6667064B2 (en) * 2000-08-30 2003-12-23 Pilot Therapeutics, Inc. Composition and method for treatment of hypertriglyceridemia
MXPA03004818A (en) * 2000-11-29 2003-09-10 Smithkline Beecham Corp Composition containing statins and calcium for improved cardiovascular health.
EP1395254B1 (en) * 2001-06-12 2007-04-04 Galephar M/F Oral pharmaceutical composition containing a statin derivative
CA2456034A1 (en) * 2001-08-03 2003-02-20 Takeda Chemical Industries, Ltd. Sustained-release medicines
WO2003103640A1 (en) 2002-06-10 2003-12-18 Elan Pharma International, Ltd Nanoparticulate formulations comprising hmg coa reductase inhibitor derivatives (“statins”), novel combinations thereof as well as manufacturing of these pharmaceutical compositions
GB0217306D0 (en) * 2002-07-25 2002-09-04 Novartis Ag Compositions comprising organic compounds
EP1551382A4 (en) * 2002-09-27 2007-01-24 Martek Biosciences Corp Prophylactic docosahexaenoic acid therapy for patients with subclinical inflammation
ES2665464T3 (en) * 2003-03-28 2018-04-25 Sigmoid Pharma Limited Solid oral dosage form containing seamless microcapsules

Also Published As

Publication number Publication date
EA012371B1 (en) 2009-10-30
JP4976302B2 (en) 2012-07-18
KR20070083715A (en) 2007-08-24
BRPI0516152A (en) 2008-08-26
ES2347055T3 (en) 2010-10-25
AU2005298587B2 (en) 2010-08-05
US20090196920A1 (en) 2009-08-06
IL182466A (en) 2013-06-27
PL1803440T3 (en) 2010-12-31
CN101043873A (en) 2007-09-26
DE602005021668D1 (en) 2010-07-15
AU2005298587A1 (en) 2006-05-04
CN102727462A (en) 2012-10-17
EA200700614A1 (en) 2007-10-26
SI1803440T1 (en) 2010-10-29
IL182466A0 (en) 2007-07-24
EP1803440A1 (en) 2007-07-04
ZA200703509B (en) 2008-09-25
JP2008517040A (en) 2008-05-22
NZ554265A (en) 2010-12-24
ES2255426B1 (en) 2007-08-16
ES2255426A1 (en) 2006-06-16
MX2007004655A (en) 2008-03-10
PT1803440E (en) 2010-08-31
KR101413339B1 (en) 2014-06-27
CA2583756C (en) 2013-12-24
ATE469641T1 (en) 2010-06-15
CY1110751T1 (en) 2015-06-10
DK1803440T3 (en) 2010-10-04
WO2006045865A1 (en) 2006-05-04
CA2583756A1 (en) 2006-05-04

Similar Documents

Publication Publication Date Title
EP1803440B1 (en) Pharmaceutical formulation comprising microcapsules of statins suspended in alkyl esters of polyunsaturated fatty asids (pufa)
ES2364011B1 (en) CAPSULES OF PHARMACEUTICAL ACTIVE AND ESTERS OF POLYINSATURATED FATTY ACIDS FOR THE TREATMENT OF CARDIOVASCULAR DISEASES.
JP5829607B2 (en) Formulation of ω3 fatty acid
JP2004518709A5 (en)
CA2874455C (en) Multilayer coating form of orally administered pharmaceutical composition containing omega-3 fatty acid or alkyl ester thereof and statin based drug
TW201138862A (en) Beta-blocking active ingredient capsules and polyunsaturated fatty acid esters
JP5725884B2 (en) Oral preparation
JP2005508369A (en) Microcapsule matrix microspheres, pharmaceutical compositions and methods for promoting absorption
EP2441445A1 (en) Coating of cetyl myristate and/or cetyl palmitate particles

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20070402

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

RIN1 Information on inventor provided before grant (corrected)

Inventor name: CARMINATI, PAOLO

Inventor name: PARENTE, ANTONIO

DAX Request for extension of the european patent (deleted)
RIC1 Information provided on ipc code assigned before grant

Ipc: A61K 9/48 20060101ALI20080912BHEP

Ipc: A61P 3/06 20060101ALI20080912BHEP

Ipc: A61K 9/50 20060101AFI20080912BHEP

Ipc: A61K 9/16 20060101ALI20080912BHEP

Ipc: A61K 31/20 20060101ALI20080912BHEP

17Q First examination report despatched

Effective date: 20090427

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: DEFIANTE FARMACEUTICA S.A.

Owner name: GP PHARM S.A.

GRAC Information related to communication of intention to grant a patent modified

Free format text: ORIGINAL CODE: EPIDOSCIGR1

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

RTI1 Title (correction)

Free format text: PHARMACEUTICAL FORMULATION COMPRISING MICROCAPSULES OF STATINS SUSPENDED IN ALKYL ESTERS OF POLYUNSATURATED FATTY ASIDS (PUFA)

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REF Corresponds to:

Ref document number: 602005021668

Country of ref document: DE

Date of ref document: 20100715

Kind code of ref document: P

REG Reference to a national code

Ref country code: CH

Ref legal event code: NV

Representative=s name: FIAMMENGHI-FIAMMENGHI

REG Reference to a national code

Ref country code: RO

Ref legal event code: EPE

REG Reference to a national code

Ref country code: PT

Ref legal event code: SC4A

Free format text: AVAILABILITY OF NATIONAL TRANSLATION

Effective date: 20100825

REG Reference to a national code

Ref country code: SE

Ref legal event code: TRGR

REG Reference to a national code

Ref country code: NL

Ref legal event code: T3

REG Reference to a national code

Ref country code: DK

Ref legal event code: T3

REG Reference to a national code

Ref country code: EE

Ref legal event code: FG4A

Ref document number: E004468

Country of ref document: EE

Effective date: 20100819

REG Reference to a national code

Ref country code: GR

Ref legal event code: EP

Ref document number: 20100402045

Country of ref document: GR

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2347055

Country of ref document: ES

Kind code of ref document: T3

REG Reference to a national code

Ref country code: PL

Ref legal event code: T3

REG Reference to a national code

Ref country code: HU

Ref legal event code: AG4A

Ref document number: E008822

Country of ref document: HU

REG Reference to a national code

Ref country code: SK

Ref legal event code: T3

Ref document number: E 8625

Country of ref document: SK

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20110303

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602005021668

Country of ref document: DE

Effective date: 20110302

REG Reference to a national code

Ref country code: PT

Ref legal event code: PC4A

Owner name: SIGMA-TAU INDUSTRIE FARMACEUTICHE RIUNITE S.P., IT

Effective date: 20141107

REG Reference to a national code

Ref country code: GB

Ref legal event code: 732E

Free format text: REGISTERED BETWEEN 20141120 AND 20141126

REG Reference to a national code

Ref country code: HU

Ref legal event code: FH1C

Free format text: FORMER REPRESENTATIVE(S): DR. LANG TIVADARNE, S.B.G. & K. SZABADALMI UEGYVIVOEI IRODA, HU

Representative=s name: SBGK SZABADALMI UEGYVIVOEI IRODA, HU

Ref country code: HU

Ref legal event code: FH1C

Free format text: FORMER REPRESENTATIVE(S): DR. LANG TIVADARNE, S.B.G. & K. SZABADALMI UEGYVIVOEI IRODA, HU

Representative=s name: DR. KOCSOMBA NELLI UEGYVEDI IRODA, HU

Ref country code: HU

Ref legal event code: GB9C

Owner name: GP PHARM S.A., ES

Free format text: FORMER OWNER(S): DEFIANTE FARMACIUTICA S.A., PT

Ref country code: HU

Ref legal event code: GB9C

Owner name: SIGMA-TAU INDUSTRIE FARMACEUTICHE RIUNITE S.P., IT

Free format text: FORMER OWNER(S): DEFIANTE FARMACIUTICA S.A., PT

REG Reference to a national code

Ref country code: DE

Ref legal event code: R081

Ref document number: 602005021668

Country of ref document: DE

Owner name: SIGMA-TAU INDUSTRIE FARMACEUTICHE RIUNITE SPA, IT

Free format text: FORMER OWNER: GP PHARM S.A., DEFIANTE FARMACEUTICA LDA., , PT

Effective date: 20150212

Ref country code: DE

Ref legal event code: R081

Ref document number: 602005021668

Country of ref document: DE

Owner name: GP PHARM S.A., ES

Free format text: FORMER OWNER: GP PHARM S.A., DEFIANTE FARMACEUTICA LDA., , PT

Effective date: 20150212

Ref country code: DE

Ref legal event code: R081

Ref document number: 602005021668

Country of ref document: DE

Owner name: GP PHARM S.A., ES

Free format text: FORMER OWNERS: GP PHARM S.A., BARCELONA, ES; DEFIANTE FARMACEUTICA LDA., FUNCHAL, PT

Effective date: 20150212

Ref country code: DE

Ref legal event code: R081

Ref document number: 602005021668

Country of ref document: DE

Owner name: SIGMA-TAU INDUSTRIE FARMACEUTICHE RIUNITE SPA, IT

Free format text: FORMER OWNERS: GP PHARM S.A., BARCELONA, ES; DEFIANTE FARMACEUTICA LDA., FUNCHAL, PT

Effective date: 20150212

REG Reference to a national code

Ref country code: CH

Ref legal event code: PFUS

Owner name: SIGMA-TAU INDUSTRIE FARMACEUTICHE RIUNITE S.P., ES

Free format text: FORMER OWNER: DEFIANTE FARMACEUTICA S.A., ES

REG Reference to a national code

Ref country code: EE

Ref legal event code: GB1A

Ref document number: E004468

Country of ref document: EE

REG Reference to a national code

Ref country code: ES

Ref legal event code: PC2A

Owner name: SIGMA-TAU INDUSTRIE FAMACEUTICHE RIUNITE, S.P.A.

Effective date: 20150622

REG Reference to a national code

Ref country code: SI

Ref legal event code: SP73

Owner name: GP PHARM S.A.; IT

Effective date: 20150618

REG Reference to a national code

Ref country code: AT

Ref legal event code: PC

Ref document number: 469641

Country of ref document: AT

Kind code of ref document: T

Owner name: GP PHARM S.A., ES

Effective date: 20150728

Ref country code: AT

Ref legal event code: PC

Ref document number: 469641

Country of ref document: AT

Kind code of ref document: T

Owner name: SIGMA-TAU INDUSTRIE FARMACEUTICHE RIUNITE S.P., IT

Effective date: 20150728

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 11

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 12

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: MC

Payment date: 20160922

Year of fee payment: 12

Ref country code: EE

Payment date: 20160926

Year of fee payment: 12

Ref country code: LT

Payment date: 20160920

Year of fee payment: 12

Ref country code: IS

Payment date: 20160920

Year of fee payment: 12

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: PL

Payment date: 20160922

Year of fee payment: 12

Ref country code: CZ

Payment date: 20160929

Year of fee payment: 12

Ref country code: LV

Payment date: 20160923

Year of fee payment: 12

Ref country code: SK

Payment date: 20160921

Year of fee payment: 12

Ref country code: RO

Payment date: 20160922

Year of fee payment: 12

Ref country code: PT

Payment date: 20160923

Year of fee payment: 12

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: TR

Payment date: 20160923

Year of fee payment: 12

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 20161027

Year of fee payment: 12

Ref country code: NL

Payment date: 20161026

Year of fee payment: 12

Ref country code: DK

Payment date: 20161025

Year of fee payment: 12

Ref country code: FI

Payment date: 20161027

Year of fee payment: 12

Ref country code: DE

Payment date: 20161027

Year of fee payment: 12

Ref country code: GB

Payment date: 20161027

Year of fee payment: 12

Ref country code: FR

Payment date: 20161025

Year of fee payment: 12

Ref country code: CY

Payment date: 20160923

Year of fee payment: 12

Ref country code: HU

Payment date: 20160929

Year of fee payment: 12

Ref country code: LU

Payment date: 20161103

Year of fee payment: 12

Ref country code: IE

Payment date: 20161028

Year of fee payment: 12

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SI

Payment date: 20160922

Year of fee payment: 12

Ref country code: BG

Payment date: 20161028

Year of fee payment: 12

Ref country code: ES

Payment date: 20161026

Year of fee payment: 12

Ref country code: SE

Payment date: 20161027

Year of fee payment: 12

Ref country code: AT

Payment date: 20160921

Year of fee payment: 12

Ref country code: GR

Payment date: 20161027

Year of fee payment: 12

Ref country code: BE

Payment date: 20161027

Year of fee payment: 12

Ref country code: IT

Payment date: 20161024

Year of fee payment: 12

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 602005021668

Country of ref document: DE

REG Reference to a national code

Ref country code: LT

Ref legal event code: MM4D

Effective date: 20171013

REG Reference to a national code

Ref country code: EE

Ref legal event code: MM4A

Ref document number: E004468

Country of ref document: EE

Effective date: 20171031

REG Reference to a national code

Ref country code: DK

Ref legal event code: EBP

Effective date: 20171031

REG Reference to a national code

Ref country code: SE

Ref legal event code: EUG

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20171031

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

REG Reference to a national code

Ref country code: NL

Ref legal event code: MM

Effective date: 20171101

REG Reference to a national code

Ref country code: AT

Ref legal event code: MM01

Ref document number: 469641

Country of ref document: AT

Kind code of ref document: T

Effective date: 20171013

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20171013

REG Reference to a national code

Ref country code: SK

Ref legal event code: MM4A

Ref document number: E 8625

Country of ref document: SK

Effective date: 20171013

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

Effective date: 20180629

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20171013

Ref country code: CZ

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20171013

Ref country code: PT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20180413

Ref country code: FI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20171013

Ref country code: EE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20171031

Ref country code: NL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20171101

Ref country code: CY

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20171013

Ref country code: SK

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20171013

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20171031

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20171013

Ref country code: LT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20171013

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20171031

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20180501

REG Reference to a national code

Ref country code: SI

Ref legal event code: KO00

Effective date: 20180605

REG Reference to a national code

Ref country code: BE

Ref legal event code: MM

Effective date: 20171031

Ref country code: BE

Ref legal event code: PD

Owner name: SIGMA-TAU INDUSTRIE FARMACEUTICHE RIUNITE S.P.A.;

Free format text: DETAILS ASSIGNMENT: CHANGE OF OWNER(S), FUSIONNER, ABSORPTION; FORMER OWNER NAME: DEFIANTE FARMACEUTICA, S.A.

Effective date: 20141120

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20180504

Ref country code: HU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20171014

Ref country code: AT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20171013

Ref country code: RO

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20171013

Ref country code: SE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20171014

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20171031

Ref country code: LV

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20171013

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20180501

Ref country code: SI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20171014

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20171031

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20171013

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20171013

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20171031

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20181220

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BG

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20180506

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20171014

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20171013

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20171013